The invention is directed to a process for the preparation of the compound of formula,
i.e. 2-(2-amino-5-chlorophenyl)-1,1,1-trifluoro-4-cyclopropyl-but-3-yn-2-ol (SD573). This compound is an important intermediate for the preparation of (−)-6-chloro-4-(cyclopropyl-ethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, which is a potent reverse transcriptase inhibitor for the treatment of HI viruses.
Jiang et al. disclosed in Tetrahedron Lett. 2002, 43, 8323-8325 and J. Org. Chem. 2002, 67, 9449-9451 the reaction of acetylene derivatives with aldehydes and ketones in the presence of equimolar amounts of a zinc(II) compound to give several racemic propargylic alcohols. Chiral compounds are not mentioned at all.
WO-A-95/20389, WO-A-96/37457, WO 98/30543 and WO 98/30540 disclose several processes for the production of chiral propargylic alcohols useful for the synthesis of pharmaceuticals. WO-A-98/51676 discloses a process wherein by addition of a first chiral and optionally a second additive in a zinc(II) mediated reaction the chiral product is obtained in high enantiomeric excess. The disadvantage of said process is the use of high amounts of expensive zinc catalysts and chiral compounds.
WO-A-2004/87628 further discloses facultative use of a chiral auxiliary in an equivalent molar amount in respect of the zinc(II) compound for the production of chiral propargylic alcohols mentioned above.
A main problem to be solved was therefore to supply an alternative process for the production of DMP266. A further problem was to reduce the amounts of catalyst and other components to be added during the reaction, in order to facilitate the workup procedures of the product and to promote industrial production.